Publication: Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Thomas R. Cox, Apr 2017

ROCK-ing pancreatic cancer to the core

Our new paper on short-term pulsed treatment, or ‘priming’ as a treatment strategy to boost chemotherapy has just been published in Science Translational Medicine.

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STM Front Cover Vol 9 Issue 384 (Image: Timpson Laboratory, Garvan Institute)

 

The research, spearheaded by Dr. Paul Timpson and Dr. Marina Pajic here at the Garvan Institute of Medical Research in Sydney, has uncovered a promising new approach to treating pancreatic cancer. By targeting the tissue surrounding the tumour to make it ‘softer’, it leads to tumours being more responsive to chemotherapy.

What we did…

As part of a large multi-disciplinary team we showed that short-term treatment, or ‘priming’ of pancreatic tumours with a three day course of an already approved drug Fasudil, increased the response rate of these tumours to standard-of-care chemotherapy (gemcitabine/Abraxane). Most notably, this sequential two-step approach acted to double the survival time and also significantly impaired the spread of cancer to other tissues.

What does this mean?

For years, researchers have been looking for ways to improve the response rate of tumours to chemotherapy drugs. This has been classically done by combining different drugs together at the same. However, whilst this does work in some cases, there are often severe side effects for the patient which means treatment must be stopped. Our research shows that rather than combining drugs at the same time, treating in a sequential (one after the other) approach is more effective and may help limit the severity of side effects. Furthermore, but targeting the tissue around the tumour first, then hitting the tumour second we see a significant improvement in response.

Perhaps the most exciting part is that Fasudil is already in clinical use as a treatment for stroke in Japan meaning it has already been proved to be safe and well tolerated in patients.  In addition to this, it is “off-patent”, meaning that the rights to use the drug are no longer owned by a Pharmaceutical drug company and so it could easily and cheaply be repurposed for the treatment of pancreatic cancer.

The road ahead

Our research marks one of the first steps along the road to bringing new treatments in pancreatic cancer to patients. By working closely with expert clinician-scientists within The Kinghorn Cancer Centre here at the Garvan Institute of Medical Research and St. Vincent’s Hospital Sydney, we are now planning establish a Phase I clinical trial within our dedicated Clinical Trials Unit. This will allow us to translate our scientific findings into an early-stage clinical study to examine the safety of our new ‘priming’ approach.

Abstract

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or “priming,” using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

Links

View the abstract in PubMed
View the article on the Science Translational Medicine website

Citation

Vennin C et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis
Science Translational Medicine  05 Apr 2017: Vol. 9, Issue 384, eaai8504

doi: 10.1126/scitranslmed.aai8504.

Funding

This study was supported by the National Health and Medical Research Council (NHMRC), Cancer Council NSW, Cancer Australia, Tour de Cure grants, Cancer Institute NSW, the Australian Research Council Future Fellowships, The Avner Pancreatic Cancer Foundation, Lens Ainsworth and Philip Hemstritch Pancreatic Cancer Fellowships, Sydney Catalyst scholarships, Royal Australasian College of Physicians Research Foundation scholarships, Pancare Australia stipend, NHMRC scholarships, a Cancer Research UK core grant, and a Patricia Helen Guest Fellowship.